Calbindin

Last updated
calbindin 1, 28kDa
Calbindin2G9B.pdb.png
NMR solution structure of Ca2+-loaded calbindin D28K. [1]
Identifiers
SymbolCALB1
Alt. symbolsCALB
NCBI gene 793
HGNC 1434
OMIM 114050
RefSeq NM_004929
UniProt P05937
Other data
Locus Chr. 8 p11
Search for
Structures Swiss-model
Domains InterPro
calbindin 2, 29kDa (calretinin)
Identifiers
SymbolCALB2
NCBI gene 794
HGNC 1435
OMIM 114051
RefSeq NM_001740
UniProt P22676
Other data
Locus Chr. 16 q22.1
Search for
Structures Swiss-model
Domains InterPro

Calbindins are three different calcium-binding proteins: calbindin, calretinin and S100G. They were originally described as vitamin D-dependent calcium-binding proteins in the intestine and kidney of chicks and mammals. They are now classified in different subfamilies as they differ in the number of Ca2+ binding EF hands.

Contents

Calbindin 1

Calbindin 1 or simply calbindin was first shown to be present in the intestine in birds and then found in the mammalian kidney. It is also expressed in a number of neuronal and endocrine cells, particularly in the cerebellum. It is a 28 kDa protein encoded in humans by the CALB1 gene.

Calbindin contains 4 active calcium-binding domains, and 2 modified domains that have lost their calcium-binding capacity. Calbindin acts as a calcium buffer and calcium sensor and can hold four Ca2+ in the EF-hands of loops EF1, EF3, EF4 and EF5. The structure of rat calbindin was originally solved by nuclear magnetic resonance and was one of the largest proteins then to be determined by this technique. [1] The sequence of calbindin is 263 residues in length and has only one chain. The sequence consists mostly of alpha helices but beta sheets are not absent. According to the NMR PDB (PDB entry 2G9B) [2] it is 44% helical with 14 helices containing 117 residues, and 4% beta sheet with 9 strands containing 13 residues.

In 2018 the X-ray crystal structure of human calbindin was published (PDB entry 6FIE). [3] [4] There were differences observed between the nuclear magnetic resonance and crystal structure despite 98% sequence identity between the rat and human isoforms. Small angle X-ray scattering indicates that the crystal structure better predicts the properties of calbindin in solution compared with the structure determined by nuclear magnetic resonance.

Calbindin is a vitamin D–responsive gene in many tissues, in particular the chick intestine, where it has a clear function in mediating calcium absorption. [5] In the brain, its synthesis is independent of vitamin-D.

Calbindin 2 (Calretinin)

Calretinin, also known as calbindin 2, is a 29 kDa protein with 58% homology to calbindin 1 and principally found in nervous tissues. [6] It is encoded in humans by the CALB2 gene and was formerly known as calbindin-D29k.

Calbindin 3 (S100G)

S100G, formerly calbindin 3 and calbindin-D9k, is present in mammalian enterocytes (epithelial cells of the intestine). S100G can also be found in the kidney and uterus in some mammalian species. It is encoded in humans by the S100G gene which has also been termed CALB3. Nonetheless, there is no homology between calbindin 1 and S100G, apart from their calcium binding domains (EF-hands): S100G has two EF-hands, and calbindin 1 has six. Unlike calbindin 1 and 2, S100G is a member of the S100 family of calcium-binding proteins.

S100G mediates the transport of calcium across the enterocytes from the apical side, where entry is regulated by the calcium channel TRPV6, to the basolateral side, where calcium pumps such as PMCA1 utilize intracellular adenosine triphosphate to pump calcium into the blood. [7] The transport of calcium across the enterocyte cytoplasm appears to be rate-limiting for calcium absorption in the intestine; the presence of calbindin increases the amount of calcium crossing the cell without raising the free concentration. [8] S100G may also stimulate the basolateral calcium-pumping ATPases. Expression of S100G, like that of calbindin 1, is stimulated by the active vitamin D metabolite, calcitriol although the precise mechanisms are still controversial. [9] In mice in which the vitamin D receptor is not expressed, S100G is less abundant, but not absent.[ citation needed ]

Discovery

Vitamin D-dependent calcium binding proteins were discovered in the cytosolic fractions of chicken intestine, and later in mammalian intestine and kidney, by researchers including Robert Wasserman of Cornell University. [10] [11] Such proteins bound calcium in the micromolar range and were greatly reduced in vitamin D-deficient animals. Expression could be induced by treating these animals with vitamin D metabolites such as calcitriol.

They were found to exist in two distinct sizes with a molecular weight of approximately 9 kDa and 28 kDa, and they were renamed calbindins.

Related Research Articles

In cellular biology, active transport is the movement of molecules or ions across a cell membrane from a region of lower concentration to a region of higher concentration—against the concentration gradient. Active transport requires cellular energy to achieve this movement. There are two types of active transport: primary active transport that uses adenosine triphosphate (ATP), and secondary active transport that uses an electrochemical gradient. This process is in contrast to passive transport, which allows molecules or ions to move down their concentration gradient, from an area of high concentration to an area of low concentration, without energy.

<span class="mw-page-title-main">Calmodulin</span> Messenger protein

Calmodulin (CaM) (an abbreviation for calcium-modulated protein) is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells. It is an intracellular target of the secondary messenger Ca2+, and the binding of Ca2+ is required for the activation of calmodulin. Once bound to Ca2+, calmodulin acts as part of a calcium signal transduction pathway by modifying its interactions with various target proteins such as kinases or phosphatases.

<span class="mw-page-title-main">Intrinsic factor</span> Glycoprotein produced in the stomach which binds to vitamin B12

Intrinsic factor (IF), cobalamin binding intrinsic factor, also known as gastric intrinsic factor (GIF), is a glycoprotein produced by the parietal cells (in humans) or chief cells (in rodents) of the stomach. It is necessary for the absorption of vitamin B12 later on in the distal ileum of the small intestine. In humans, the gastric intrinsic factor protein is encoded by the CBLIF gene. Haptocorrin (transcobalamin I) is another glycoprotein secreted by the salivary glands which binds to vitamin B12. Vitamin B12 is acid-sensitive and in binding to haptocorrin it can safely pass through the acidic stomach to the duodenum.

<span class="mw-page-title-main">Parathyroid hormone</span> Mammalian protein found in humans

Parathyroid hormone (PTH), also called parathormone or parathyrin, is a peptide hormone secreted by the parathyroid glands that regulates the serum calcium concentration through its effects on bone, kidney, and intestine.

<span class="mw-page-title-main">Calcium metabolism</span> Movement and regulation of calcium ions in and out of the body

Calcium metabolism is the movement and regulation of calcium ions (Ca2+) in (via the gut) and out (via the gut and kidneys) of the body, and between body compartments: the blood plasma, the extracellular and intracellular fluids, and bone. Bone acts as a calcium storage center for deposits and withdrawals as needed by the blood via continual bone remodeling.

<span class="mw-page-title-main">Enterocyte</span> Type of intestinal cell

Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells which line the inner surface of the small and large intestines. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase its surface area. This facilitates transport of numerous small molecules into the enterocyte from the intestinal lumen. These include broken down proteins, fats, and sugars, as well as water, electrolytes, vitamins, and bile salts. Enterocytes also have an endocrine role, secreting hormones such as leptin.

<span class="mw-page-title-main">Calcitriol</span> Active form of vitamin D

Calcitriol is a hormone and the active form of vitamin D, normally made in the kidney. It is also known as 1,25-dihydroxycholecalciferol. It binds to and activates the vitamin D receptor in the nucleus of the cell, which then increases the expression of many genes. Calcitriol increases blood calcium mainly by increasing the uptake of calcium from the intestines.

<span class="mw-page-title-main">TRPV6</span> Protein-coding gene in the species Homo sapiens

TRPV6 is a membrane calcium (Ca2+) channel protein which is particularly involved in the first step in Ca2+absorption in the intestine.

Oncomodulin is a parvalbumin-family calcium-binding protein expressed and secreted by macrophages.

<span class="mw-page-title-main">Hephaestin</span> Mammalian protein found in Homo sapiens

Hephaestin, also known as HEPH, is a protein which in humans is encoded by the HEPH gene.

<span class="mw-page-title-main">EF hand</span> Protein helix–loop–helix motif

The EF hand is a helix–loop–helix structural domain or motif found in a large family of calcium-binding proteins.

Calcium-binding proteins are proteins that participate in calcium cell signaling pathways by binding to Ca2+, the calcium ion that plays an important role in many cellular processes. Calcium-binding proteins have specific domains that bind to calcium and are known to be heterogeneous.

<span class="mw-page-title-main">Calretinin</span> Protein found in humans

Calretinin, also known as calbindin 2, is a calcium-binding protein involved in calcium signaling. In humans, the calretinin protein is encoded by the CALB2 gene.

<span class="mw-page-title-main">Parvalbumin</span> Calcium-binding protein with low molecular weight

Parvalbumin (PV) is a calcium-binding protein with low molecular weight. In humans, it is encoded by the PVALB gene. It is a member of the albumin family; it is named for its size and its ability to coagulate.

<span class="mw-page-title-main">S100P</span> Protein-coding gene in the species Homo sapiens

S100 calcium-binding protein P (S100P) is a protein that in humans is encoded by the S100P gene.

<span class="mw-page-title-main">S100G</span> Protein-coding gene in the species Homo sapiens

S100 calcium-binding protein G (S100G) is a protein that in humans is encoded by the S100G gene.

<span class="mw-page-title-main">Secretagogin</span> Protein-coding gene in the species Homo sapiens

Secretagogin is a protein that in humans is encoded by the SCGN gene.

<span class="mw-page-title-main">Intestinal epithelium</span> Single-cell layer lining the intestines

The intestinal epithelium is the single cell layer that forms the luminal surface (lining) of both the small and large intestine (colon) of the gastrointestinal tract. Composed of simple columnar epithelium its main functions are absorption, and secretion. Useful substances are absorbed into the body, and the entry of harmful substances is restricted. Secretions include mucins, and peptides.

<span class="mw-page-title-main">Calbindin 1</span> Protein found in humans

Calbindin 1 is a protein that in humans is encoded by the CALB1 gene. It belongs to the calbindin family of calcium-binding proteins, along with calretinin (CALB2).

Robert Harold Wasserman was a professor of veterinary medicine and a research scientist, known as the principal investigator leading the scientists credited with the discovery of calcium-binding proteins.

References

  1. 1 2 PDB: 2G9B ​; Kojetin DJ, Venters RA, Kordys DR, Thompson RJ, Kumar R, Cavanagh J (July 2006). "Structure, binding interface and hydrophobic transitions of Ca2+-loaded calbindin-D(28K)". Nature Structural & Molecular Biology. 13 (7): 641–7. doi:10.1038/nsmb1112. PMID   16799559. S2CID   29426332.
  2. ↑ Kojetin, Douglas J; Venters, Ronald A; Kordys, David R; Thompson, Richele J; Kumar, Rajiv; Cavanagh, John (July 2006). "Structure, binding interface and hydrophobic transitions of Ca2+-loaded calbindin-D28K". Nature Structural & Molecular Biology. 13 (7): 641–647. doi:10.1038/nsmb1112. ISSN   1545-9993. PMID   16799559. S2CID   29426332.
  3. ↑ Noble, J. W.; Almalki, R.; Roe, S. M.; Wagner, A.; Duman, R.; Atack, J. R. (2018). "The X-ray structure of human calbindin-D28K: an improved model". Acta Crystallogr D. 74 (Pt 10): 1008–1014. doi:10.2210/pdb6fie/pdb. PMC   6173056 . PMID   30289411.
  4. ↑ Noble JW, Almalki R, Roe SM, Wagner A, Duman R, Atack JR (October 2018). "The X-ray structure of human calbindin-D28K: an improved model". Acta Crystallographica Section D. 74 (Pt 10): 1008–1014. Bibcode:2018AcCrD..74.1008N. doi:10.1107/S2059798318011610. PMC   6173056 . PMID   30289411.
  5. ↑ Wasserman RH, Fullmer CS (1989). "On the Molecular Mechanism of Intestinal Calcium Transport". Mineral Absorption in the Monogastric GI Tract. Advances in Experimental Medicine and Biology. Vol. 249. pp. 45–65. doi:10.1007/978-1-4684-9111-1_5. ISBN   978-1-4684-9113-5. PMID   2543194.
  6. ↑ Rogers JH (September 1987). "Calretinin: a gene for a novel calcium-binding protein expressed principally in neurons". The Journal of Cell Biology. 105 (3): 1343–53. doi:10.1083/jcb.105.3.1343. PMC   2114790 . PMID   3654755.
  7. ↑ Wasserman RH, Chandler JS, Meyer SA, Smith CA, Brindak ME, Fullmer CS, et al. (March 1992). "Intestinal calcium transport and calcium extrusion processes at the basolateral membrane". The Journal of Nutrition. 122 (3 Suppl): 662–71. doi: 10.1093/jn/122.suppl_3.662 . PMID   1311756.
  8. ↑ Feher JJ, Fullmer CS, Wasserman RH (February 1992). "Role of facilitated diffusion of calcium by calbindin in intestinal calcium absorption". The American Journal of Physiology. 262 (2 Pt 1): C517-26. doi:10.1152/ajpcell.1992.262.2.C517. PMID   1539638.
  9. ↑ Barley NF, Prathalingam SR, Zhi P, Legon S, Howard A, Walters JR (August 1999). "Factors involved in the duodenal expression of the human calbindin-D9k gene". The Biochemical Journal. 341 ( Pt 3) (3): 491–500. doi:10.1042/0264-6021:3410491. PMC   1220384 . PMID   10417310.
  10. ↑ Wasserman RH, Taylor AN (May 1966). "Vitamin d3-induced calcium-binding protein in chick intestinal mucosa". Science. 152 (3723): 791–3. Bibcode:1966Sci...152..791W. doi:10.1126/science.152.3723.791. PMID   17797460. S2CID   8221178.
  11. ↑ Wasserman RH, Corradino RA, Taylor AN (July 1969). "Binding proteins from animals with possible transport function". The Journal of General Physiology. 54 (1): 114–37. doi:10.1085/jgp.54.1.114. PMC   2225897 . PMID   19873640.

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